Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction
Nicola Wilck, Lajos Markó, András Balogh, Kristin Kräker, Florian Herse, Hendrik Bartolomaeus, István A. Szijártó, Maik Gollasch, Nadine Reichhart, Olaf Strauss, Arnd Heuser, Damian Brockschnieder, Axel Kretschmer, Ralf Lesche, Florian Sohler, Johannes-Peter Stasch, Peter Sandner, Friedrich C. Luft, Dominik N. Müller, Ralf Dechend, Nadine Haase
Nicola Wilck, Lajos Markó, András Balogh, Kristin Kräker, Florian Herse, Hendrik Bartolomaeus, István A. Szijártó, Maik Gollasch, Nadine Reichhart, Olaf Strauss, Arnd Heuser, Damian Brockschnieder, Axel Kretschmer, Ralf Lesche, Florian Sohler, Johannes-Peter Stasch, Peter Sandner, Friedrich C. Luft, Dominik N. Müller, Ralf Dechend, Nadine Haase
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Research Article Cardiology

Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide–sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.

Authors

Nicola Wilck, Lajos Markó, András Balogh, Kristin Kräker, Florian Herse, Hendrik Bartolomaeus, István A. Szijártó, Maik Gollasch, Nadine Reichhart, Olaf Strauss, Arnd Heuser, Damian Brockschnieder, Axel Kretschmer, Ralf Lesche, Florian Sohler, Johannes-Peter Stasch, Peter Sandner, Friedrich C. Luft, Dominik N. Müller, Ralf Dechend, Nadine Haase

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Figure 1

NOsGC stimulation reduces blood pressure and improves endothelial function and survival.

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NOsGC stimulation reduces blood pressure and improves endothelial functi...
(A) Kaplan-Meier survival analysis of vehicle-treated dTGR and dTGR receiving BAY 41-8543. At week 7, only 24% of vehicle-treated dTGR survived. BAY 41-8543 improved the survival of the dTGR to 100%. Survival curves are statistically different by the log-rank test (P < 0.0001). No SD rats died before end of study (data not shown). (B) Rats were weighed daily. Vehicle-treated dTGR lost weight significantly from week 6 to week 7. In SD rats and BAY 41-8543–treated dTGR, no change in weight was observed (#P < 0.05,between all groups, 2-way ANOVA with Bonferroni post hoc test; *P < 0.05 vehicle vs. BAY 41-8543 and SD, Bonferroni post hoc test; data expressed as mean ± SEM; SD, n = 6; vehicle, n = 4-13; BAY 41-8543, n = 12). (C) Tail-cuff systolic blood pressure (SBP) at weeks 5, 6, and 7. SBP increased in vehicle-treated dTGR. BAY 41-8543 significantly reduced SBP. SD rats were normotensive (#P < 0.05, *P < 0.01 vehicle vs. BAY 41-8543 and SD, +P < 0.01 BAY 41-8543 vs. SD; data expressed as mean ± SEM; 2-way ANOVA with Bonferroni post hoc test; SD, n = 6; vehicle, n = 6; BAY 41-8543, n = 12). (D) Radiometric telemetry SBP over 24 hours on day 21 of treatment. Data are expressed as AUC in vehicle- and BAY 41-8543–treated dTGR. BAY 41-8543 significantly reduced SBP (*P < 0.05; Mann Whitney U test; data expressed as mean ± SEM; vehicle, n = 5; BAY 41-8543, n = 4). (E) Myograph analysis on mesenteric arteries of dTGR showed in the presence of acetylcholine improved endothelial function in BAY 41-8543–treated rats compared with vehicle-treated dTGR in a dose-dependent manner (#P < 0.05, *P < 0.05 vehicle vs. BAY 41-8543; data expressed as mean ± SEM; 2-way ANOVA with Bonferroni post hoc test; vehicle, n = 31; BAY 41-8543, n = 30).